1. Technical Field
The invention relates to an improved process for the preparation of certain macrocyclic compounds useful as agents for the treatment of hepatitis C viral (HCV) infections. More specifically, the invention relates to an improved process for the preparation of such macrocyclic compounds via a ring closing metathesis (“RCM”) reaction in a gaseous fluid at supercritical or near-supercritical conditions.
2. Background Information
The macrocyclic compounds of the following formula (I) and methods for their preparation are known from: Tsantrizos et al., U.S. Pat. No. 6,608,027 B1; Llinas Brunet et al, U.S. Application Publication No. 2003/0224977 A1; Llinas Brunet et al, U.S. Application Publication No. 2005/0075279 A1; Llinas Brunet et al, U.S. Application Publication No. 2005/0080005 A1 Brandenburg et al., U.S. Application Publication No. 2005/0049187 and Samstag et al., U.S. Application Publication No. 2004/0248779 A1, :
wherein    RA is a leaving group or a group of formula II
    W is CH or N,    L0 is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, hydroxy, or N(R23)2,    wherein each R23 is independently H, C1-6 alkyl or C3-6 cycloalkyl;    L1, L2 are each independently H, halogen, C1-4alkyl, —O—C1-4alkyl, or —S—C1-4alkyl (the sulfur being in any oxidized state); or    L0 and L1 or    L0 and L2 may be covalently bonded to form together with the two C-atoms to which they are linked a 4-, 5- or 6-membered carbocyclic ring wherein one or two (in the case of a 5- or 6-membered ring) —CH2— groups not being directly bonded to each other, may be replaced each independently by —O— or NRa wherein Ra is H or C1-4alkyl, and wherein said ring is optionally mono- or di-substituted with C1-4 alkyl;    R22 is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 thioalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, C2-7 alkoxyalkyl, C3-6 cycloalkyl, C6 or C10 aryl or Het, wherein Het is a five-, six-, or seven-membered saturated or unsaturated heterocycle containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur;    said cycloalkyl, aryl or Het being substituted with R24,    wherein R24 is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, NO2, N(R25)2, NH—C(O)—R25; or NH—C(O)—NH—R25, wherein each R25 is independently: H, C1-6 alkyl or C3-6 cycloalkyl;    or R24 is NH—C(O)—OR26 wherein R26 is C1-6 alkyl or C3-6 cycloalkyl;    R3 is hydroxy, NH2, or a group of formula —NH—R9, wherein R9 is C6 or 10 aryl, heteroaryl, —C(O)—R20, —C(O)—NHR20 or —C(O)—OR20, wherein R20 is C1-6 alkyl or C3-6 cycloalkyl;    D is a 3 to 7 atom saturated alkylene chain optionally containing one to three heteroatoms independently selected from: O, S or N—R27, wherein R27 is H, C1-6alkyl, C3-6cycloalkyl or C(O)R28, wherein R28 is C1-6alkyl, C3-6cycloalkyl or C6 or 10 aryl;    R4 is H, or from one to three substituents at any carbon atom of said chain D, said substituent independently selected from the group consisting of: C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, hydroxy, halo, amino, oxo, thio, or C1-6 thioalkyl; and    A is an amide of formula —C(O)—NH—R11, wherein R11 is selected from the group consisting of: C1-8 alkyl, C3-6 cycloalkyl, C6 or 10 aryl, C7-16 aralkyl, or SO2R5A wherein R5A is C1-8 alkyl, C3-7 cycloalkyl,C1-6 alkyl-C3-7 cycloalkyl;    or A is a carboxylic acid or a pharmaceutically acceptable salt or ester thereof.
The compounds of formula (I) are disclosed in the above-mentioned patent documents as being active agents for the treatment of hepatitis C viral (HCV) infections, or as intermediates useful for the preparation of such anti-HCV agents as described therein, and are prepared therein via ring-closing metathesis of an acyclic diolefin using ruthenium-based catalysts in a suitable organic solvent.
It has been reported that supercritical carbon dioxide may be used as a versatile reaction medium for conducting certain olefin metathesis reactions, and in the case of ring-closing olefin metathesis reactions, the solubility properties of the supercritical carbon dioxide may be exploited to isolate the low molecular weight RCM products from the ruthenium complex via selective supercritical fluid extraction (Furstner et al., J. Am. Chem. Soc., 2001, 123(37), 9000; W. Leitner, C. R. Acad. Sci. Paris, Serie IIc, Chimie, 2000, 3, 595; Furstner et al., Angew. Chem., 1997, 109, 2562, and Angew. Chem. Int. Ed. Engl., 1997, 36, 2466; and Pandey et. al., J. Phys. Chem. B. 2002, 106(7), 1820). However, although numerous examples are provided using lower molecular weight RCM products, there is no disclosure or suggestion that such technique would be effective for higher molecular weight RCM products, such as the macrocyclic compounds of formula (I).